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 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.

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.

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.

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.

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.

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.

A population analysis of prescriptions for asthma medications during pregnancy.

BACKGROUND: It is important to control asthma during pregnancy. However, some studies indicate that women stop or change their asthma medications when they become pregnant. OBJECTIVE: We used a population database to analyze changes in prescriptions for asthma medications to patients before, during, and after pregnancy. METHODS: We collected information from a pregnancy database that is part of the population-based pharmacy prescription InterAction Database from the northern Netherlands. Our study cohort comprised 25,709 pregnancies for which prescription data were available. We collected data over a study period of 1 year before pregnancy until 6 months after birth and analyzed data from pregnant women who received at least 1 prescription for asthma medication during the study period (n = 2072), identifying all prescriptions for asthma medication and oral corticosteroids. RESULTS: Prescriptions for asthma medications did not change during pregnancies from 1994-2003. However, during the 2004-2009 period, there was a significant decrease (P = .017) in prescriptions for asthma medications during the first months of pregnancy compared with the months before pregnancy, especially prescriptions of long-acting bronchodilators. Although most asthma prescriptions continued throughout pregnancy, prescriptions for controller therapies were reduced by 30% during the first months of pregnancy. CONCLUSIONS: Many women stop or reduce their use of asthma medications when they become pregnant. Strategies to safely control asthma during pregnancy are needed.

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.

Valproic acid monotherapy in pregnancy and major congenital malformations.

BACKGROUND: The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited. METHODS: We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005. RESULTS: Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs. CONCLUSIONS: The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

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.

Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 2: Testing the hypotheses.

AIMS: Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS: The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children after in utero exposure to antidepressants (TCA, SSRI, fluoxetine or paroxetine exposed) was compared with no antidepressant exposure. Laxatives and antidiarrhoeal medication use were applied as a proxy for constipation and diarrhoea respectively, which may be associated with disturbed enteric nervous system (ENS) development. RESULTS: Children exposed in utero to SSRIs (mainly fluoxetine and paroxetine) in the second and third trimester or to TCAs in the first trimester, more often received laxatives. Combined exposure to TCAs and SSRIs in pregnancy was associated with a 10-fold increase in laxative use. In utero exposure to SSRIs is not associated with antidiarrhoeal medication use compared with non-exposed children. In contrast, antidiarrhoeal medication use was significantly higher in children exposed to TCAs anytime in pregnancy. CONCLUSIONS: The increased laxative use after second and third trimester exposure to SSRIs might be explained through the inhibitory effect of the serotonin re-uptake transporter (SERT) and because of selectivity for the 5-HT(2B) receptor which affects the ENS. TCA exposure during the first trimester leads to increased laxative use probably through inhibition of the norepinephrine transporter (NET). Exposure of TCAs anytime in pregnancy leads to increase diarrhoeal use possibly through down-regulation of α2-adrenoceptors or up-regulation of the pore forming α(1c) subunit.

Clomipramine concentration and withdrawal symptoms in 10 neonates.

AIM: After in utero exposure to tricyclic antidepressants, neonatal withdrawal symptoms have been reported with an estimated incidence between 20 and 50%; however, few data are available for clomipramine. This could also be the case for neonatal pharmacokinetic clomipramine parameters and so this study was set up. METHODS: Babies exposed to clomipramine in utero were included in an observational study, approved by the local ethics committee, after written informed consent. Withdrawal symptoms were scored at 12, 24 and 48 h after birth using the Finnegan score. Plasma concentrations were determined using an in-house-developed, validated liquid chromatography with mass detection (LC-MSMS) method at 0, 12, 24 and 48 h after birth. RESULTS: We found that three of 11 pregnancies were complicated with pre-eclampsia. Ten neonates were observed for clomipramine withdrawal symptoms. The observed withdrawal symptoms were too short a period of sleep after feeding (6), poor feeding (3), mild to severe tremors (6), hyperactive Moro reflex (3) and respiratory rate >60 breaths min(-1). Serious withdrawal reactions, such as tachycardia and cyanosis, were seen. We calculated a half-life value of 42 ± 16 h for clomipramine in neonates. Only a weak correlation was found between withdrawal reactions and clomipramine plasma concentration or desmethylclomipramine plasma concentration. CONCLUSIONS: In neonates, clomipramine is eliminated with a half-life value of 42 h, compared with 20 h in adults. In two of 10 neonates, tachycardia and cyanosis were seen as serious withdrawal symptoms after maternal use of clomipramine.

A comparison of pharmacoepidemiological study designs in medication use and traffic safety research.

In order to explore how the choice of different study designs could influence the risk estimates, a case-crossover and case-time-control study were carried out and their outcomes were compared with those of a traditional case-control study design that evaluated the association between the exposure to psychotropic medications and the risk of having a motor vehicle accident (MVA). A record-linkage database availing data for 3,786 cases and 18,089 controls during the period 2000-2007 was used. The study designs (i.e., case-crossover and case-time-control) were derived from published literature, and the following psychotropic medicines were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants, stratified in the two groups selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Moreover, in order to further investigate the effects of frequency of psychoactive medication exposure on the outcomes of the case-crossover analysis, the data were also stratified by the number of defined daily doses (DDDs) and days of medication use in the 12 months before the motor vehicle accident. Three-thousand seven-hundred fifty-two cases were included in this second part of the case-crossover analysis. The case-crossover design did not show any statistically significant association between psychotropic medication exposure and MVA risk [e.g., SSRIs-Adj. OR = 1.00 (95 % CI: 0.69-1.46); Anxiolytics-Adj. OR = 0.95 (95 % CI: 0.68-1.31)]. The case-time-control design only showed a borderline statistically significant increased traffic accident risk in SSRI users [Adj. OR = 1.16 (95 % CI: 1.01-1.34)]. With respect to the stratifications by the number of DDDs and days of medication use, the analyses showed no increased traffic accident risk associated with the exposure to the selected medication groups [e.g., SSRIs, <20 DDDs-Adj. OR = 0.65 (95 % CI: 0.11-3.87); SSRIs, 16-150 days-Adj. OR = 0.55 (95 % CI: 0.24-1.24)]. In contrast to the above-mentioned results, our recent case-control study found a statistically significant association between traffic accident risk and exposure to anxiolytics [Adj. OR = 1.54 (95 % CI: 1.11-2.15)], and SSRIs [Adj. OR = 2.03 (95 % CI: 1.31-3.14)]. Case-crossover and case-time-control analyses produced different results than those of our recent case-control study (i.e., case-crossover and case-time-control analyses did not show any statistically significant association whereas the case-control analysis showed an increased traffic accident risk in anxiolytic and SSRI users). These divergent results can probably be explained by the differences in the study designs. Given that the case-crossover design is only appropriate for short-term exposures and the case-time-control design is an elaboration of this latter, it can be concluded that, probably, these two approaches are not the most suitable ones to investigate the relation between MVA risk and psychotropic medications, which, on the contrary, are often use chronically.

Are antibiotics related to oral combination contraceptive failures in the Netherlands? A case-crossover study.

PURPOSE: To investigate whether there is an association between use of antibiotics and breakthrough pregnancy. METHODS: The study was performed in a population-based prescription database (IADB.nl). We computed case-crossover odds ratios of 397 cases of defined breakthrough pregnancy comparing the use of antibiotics in the exposure window with the use of antibiotics in two control windows. We defined a control group consisting of 29 022 other pregnancies. We computed case-control odds ratios of the use of antibiotics in cases as compared with controls in the different time windows. RESULTS: The case-crossover odds ratios comparing the use of antibiotics in the exposure window with both control windows were 2.21 (95%CI = 1.03-4.75) and 1.65 (95%CI = 0.78-3.48), respectively. The traditional case-control odds ratios after adjustment for age were 1.71 (95%CI = 1.09-2.66) in the exposure window, 0.81 (95%CI = 0.44-1.47) 2 months before the exposure window, and 1.04 (95%CI = 0.61-1.78) 12 months before the exposure window. CONCLUSIONS: We did find a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database. The results did not hold for broad-spectrum antibiotics or in a sensitivity analysis. The results are partly not the same as those found in a pharmacoepidemiological study with a similar design using two US pregnancy databases. Both studies can suffer from bias and confounding, but these will be different because of the use of different databases.

Prescriptive contraceptive use among isotretinoin users in the Netherlands in comparison with non-users: a drug utilisation study.

PURPOSE: To assess the compliance with the isotretinoin Pregnancy Prevention Programme (PPP) by evaluating the use of prescribed contraceptives among isotretinoin users. The PPP contains a requirement for the use of contraceptive methods for women of childbearing potential. METHODS: A drug utilisation study was performed using data from a drug prescription database (containing Dutch community pharmacy data) covering a population of 500 000 patients. Contraceptive use in female isotretinoin users and in a reference group of female non-isotretinoin users (aged 15-49 years) was compared using data from 1999 until 2006 in 2-year periods. Descriptive statistics were used. RESULTS: Of the female isotretinoin users (n = 651), 52%-54% filled prescriptions on contraceptives in strict accordance to the PPP, used before, during, and after discontinuation of isotretinoin, compared with 39%-46% in the reference group. A more liberal approach of a minimum of one prescription for a contraceptive method showed 61%-64% use of contraceptives among isotretinoin users. Similar patterns were seen when data were broken down in age groups. Furthermore, a higher proportion of female patients using isotretinoin prescribed by general practitioners used prescribed contraceptives compared with those receiving isotretinoin by specialists. CONCLUSION: Compliance with the contraceptive use according to a PPP for a teratogenic drug such as isotretinoin is 52%-64%, which is lower than anticipated. Reasons for the low compliance will need to be clarified before further measures can be taken.

Psychotropic medication during endocrine treatment for breast cancer.

PURPOSE: Psychological problems are frequently mentioned in women treated for breast cancer in whom depression is mentioned as the most common disorder. The aim was to study the prescription of psychotropic medication in women with endocrine treatment for breast cancer in women in our prospective and consecutive pharmacy database. METHODS: Women (n = 2,172) with at least one prescription of tamoxifen, fulvestrant, anastrazole, letrozole or exemestane were considered as breast cancer patients treated with endocrine therapy. This group was compared with an age- and family physician-matched group of women without cancer (n = 8,129), and the incidence risk ratio (IRR) and the 95% confidence intervals (95% CI) were calculated. In addition, the prevalence of these psychotropic medication prescriptions and the 95% CI were calculated. RESULTS: There was an increased prescription of psychotropic medication in the female breast cancer patients on endocrine therapy: anxiolytics (IRR 2.07, 95% CI 1.87-2.29), hypnotics and sedatives (IRR 2.59, 95% CI 2.34-2.87) and anti-depressants (IRR 1.46, 95% CI 1.28-1.65). The prevalences of anxiolytics, hypnotics and sedatives were also increased in this group, indicating an increased use over time of these drugs. The prevalence of anti-depressant prescription was not increased, indicating short-term use only. CONCLUSIONS: This study indicated increased psychological distress due to breast cancer diagnosis and/or treatment in women on endocrine therapy. Anti-depressants were only prescribed for a short time. These data can contribute to an improved awareness of the impact of breast cancer (treatment) and therefore potentially to the optimizing of support for these patients.

Road traffic accidents and psychotropic medication use in The Netherlands: a case-control study.

AIM: To examine the association between the use of commonly prescribed psychotropic medications and road traffic accident risk. METHODS: A record-linkage database was used to perform a case-control study in The Netherlands. The data came from three sources: pharmacy prescription data, police traffic accident data and driving licence data. Cases were defined as drivers, who had a traffic accident that required medical assistance between 2000 and 2007. Controls were defined as adults, who had a driving licence and had no traffic accident during the study period. Four controls were matched for each case. The following psychotropic medicine groups were examined: antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants stratified in the two groups, SSRIs and other antidepressants. Various variables, such as age, gender, medicine half-life and alcohol use, were considered for the analysis. RESULTS: Three thousand nine hundred and sixty-three cases and 18,828 controls were included in the case-control analysis. A significant association was found between traffic accident risk and exposure to anxiolytics (OR = 1.54, 95% CI 1.11, 2.15), and SSRIs (OR = 2.03, 95% CI 1.31, 3.14). A statistically significant increased risk was also seen in chronic anxiolytic users, females and young users (18 to 29 years old), chronic SSRI users, females and middle-aged users (30 to 59 years old), and intermediate half-life hypnotic users. CONCLUSIONS: The results of this study support previous findings and confirm that psychoactive medications can constitute a problem in traffic safety. Both health care providers and patients should be properly informed of the potential risks associated with the use of these medicines.