L. T. W. De Jong-Van Den Berg

Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations

Objective: To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk. Methods: Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995–2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use. Results: There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10–2.34) for OC relative to other malformations, 0.80 (95% CI 0.11–2.85) for isolated OC, 0.79 (95% CI 0.03–4.35) for CP, and 1.01 (95% CI 0.03–5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03–1.93) for OC, 1.21 (95% CI 0.82–1.72) for isolated OC, 2.37 (95% CI 1.54–3.43) for CP, and 1.86 (95% CI 1.07–2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed. Conclusion: We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

Compliance with pregnancy prevention programmes of isotretinoin in Europe: a systematic review

Most of the publications on isotretinoin, pregnancy and compliance with the pregnancy prevention programme (PPP) originate from North America. Information specific for the European situation is very limited. The aim of this study was to identify publications describing the use of isotretinoin in humans and the compliance with the PPP in Europe, a systematic search in Medline and Embase was conducted using the terms ‘isotretinoin, pregnancy (and Europe)’. Furthermore, a manual search in publications was performed. A total of 17 publications were identified. Publications consisted of case reports of exposed pregnancies, surveys among dermatologists or pharmacists and database studies evaluating compliance with the PPP. The studies and surveys dealt with groups of patients exposed to isotretinoin before or during pregnancy and/or compliance with the isotretinoin PPP. Where the information was provided, in 6–26% of cases isotretinoin was prescribed in full accordance with the PPP. Pregnancy incidence was seen in 0·2–1·0 per 1000 women of childbearing age using isotretinoin. Between 65% and 87% of these pregnancies were terminated. This review of studies in Europe performed to date shows failures in the implementation of the PPP. Therefore, the isotretinoin PPP must be scrutinized to identify whether new measures should be taken or whether the failures in the implementation need to be corrected. New measures should take into account the definition of the ultimate goal of a PPP and the acceptable burden. In the meantime, stakeholders could make a start with adjustments in the implementation of the PPP by taking responsibility and enhancing the performance by explicit instructions, monitoring the performance and adjusting, if necessary.

Socio-economic differences in prescription and OTC drug use in Dutch adolescents

Objective: To detect whether there were socio‐economic differences in the overall use of prescription and OTC drugs among adolescents. Methods: This study was a secondary analysis of questionnaire data collected to investigate socio‐economic differences in health risk behaviour and decision‐making. Results: About 20% of the 741 girls and 10% of the 736 boys reported using at least one prescription drug in the past 14 days, oral contraceptives excluded. For OTC drugs these percentages were 45% and 24%, respectively. No statistically significant socio‐economic differences in prescription drug use could be detected. A higher socio‐economic status was associated with an increased OTC drug use, especially in boys. The odds of girls who reported medication was about twice that for boys, after adjusting for perceived health and socio‐economic status.Conclusion: There were socio‐economic differences with regard to OTC drug use. No socio‐economic differences in prescription medication use could be found. There were gender differences with respect to medication use in adolescence, regardless of perceived health and socio‐economic status.

INVESTIGATING DRUG-USE IN PREGNANCY - METHODOLOGICAL PROBLEMS AND PERSPECTIVES

In this study the use of prescribed drugs before, during and after pregnancy is described. The study is based on data obtained from pharmacy records of 1,948 women who delivered a live-born infant. Different measures to evaluate drug exposure are used. During the nine months of pregnancy 86% of the women used on average 4.2 prescriptions. During the course of pregnancy the use of gastro-intestinal and blood-forming drugs increased, whereas the use of cardiovascular, antiphlogistic and central nervous system drugs decreased. Anti-emetics were predominantly used in the first trimester, and antacids in the last trimester, whereas laxatives were especially used after delivery. The percentage of women who used a treatment for vaginal infections increased from 2 to 7 during pregnancy. Most of the women (73%) received one or more iron prescriptions during the course of pregnancy, however, the prescribed daily dose was low (prescribed daily dose/defined daily dose=0.6). At least 1% of the women filled a new prescription for anticonceptives in the first trimester of pregnancy. Most likely, our data reflect the general prescribing pattern for Dutch pregnant women who delivered a live-born baby. Therefore, they form a good and detailed base for further studies, for instance, on the exposure to drugs with known or suspected risks or on the use of drugs in patients with chronic concomitant diseases. Such studies may lead to recommendations that may improve prescribing behaviour.

Concomitant prescribing of benzodiazepines during antidepressant therapy in the elderly

A follow-up study was performed in two ambulatory cohorts aged > or =65 to investigate whether the prevalence and incidence of anxiolytic/hypnotic benzodiazepine drug prescribing is comparable between users of serotonin reuptake inhibitors (SSRIs) and users of tricyclic antidepressants (TCAs). The prevalence and incidence of benzodiazepines during antidepressant therapy was estimated among users of TCAs and SSRIs. Coprescribing of benzodiazepines occurred in 53% of the TCA users and 57% of the SSRI users (prevalence RR 1.1; CI(95) 0.9-1.2). The average duration of benzodiazepine drug use was >65 days per 100 days of antidepressant use. During SSRI therapy, significantly more people started benzodiazepine drug therapy than during TCA therapy (incidence rate ratio (RR) 1.7; CI(95) 1.2-2.4). Analyses repeated 5 years later yielded similar results (overall incidence RR(MH) 1.6; CI(95) 1.3-2.0). These data indicate that SSRI use is associated with a significantly higher chance of starting benzodiazepines compared with TCA use.

Vulvo-vaginal candidiasis associated with acitretin

The aim of this study was to estimate the risk of vulvo-vaginal candidiasis among the users of acitretin. The incidence rate ratio of vulvo-vaginal candidiasis was estimated in a cohort of acitretin users by using prescription sequence analysis. Study subjects were 196 women between 15 and 45 years of age, exposed to acitretin in 1990. Prescriptions of drugs for treatment of vulvo-vaginal candidiasis were used as proxy for the occurrence of vulvo-vaginal candidiasis. Validation of the proxy drug was performed by record linkage of pharmacy and medical records. In addition to the risk estimation by incidence rate ratios a case-crossover study with patient-stratified logistic regression analysis was performed to control for distortion due to individual differences in contribution of exposure time. The positive predictive value of the proxy drug for vulvo-vaginal candidiasis ranged between 57 and 100%, the sensitivity was 87% and the specificity estimated 99%. The crude incidence rate ratio for vulvo-vaginal candidiasis following acitretin exposure was 2.8 (CI95%: 1.1-7.1). The pooled Mantel-Haenszel incidence rate ratio was 3.3 (CI95%: 1.1-9.6) after stratification for accumulated level of exposure. Patient-stratified analysis on the subgroup of cases (n = 15) revealed an odds ratio of 6.5 (CI95%: 2.3-18.2). This study strongly suggests that the higher occurrence of vulvo-vaginal candidiasis during acitretin exposure is attributable to the drug.

Antidepressant drug choice for first users in two regions in the Netherlands

Objective: To map the prescribing habits of physicians in two different regions in the Netherlands with respect to antidepressant drug choice for first users. Design: Retrospective follow‐up study. Methods: All persons who received an antidepressant drug for the first time during October 1994 to September 1995 were identified from 29 community pharmacies situated in two regions in the Netherlands. Age, gender, type of prescriber, region and the concomitant use of certain groups of drugs as marker for certain diseases were evaluated as determinants for prescribing either a “classic” or a “second generation” antidepressant drug to first users using logistic regression analysis. Results: We identified 4,637 first users during the study period corresponding with an overall incidence density of 16 per 1,000 person‐years. For the majority of first users of both regions, the same five antidepressants were prescribed. However, the two regions differed markedly with regard to the frequency of prescription of the individual antidepressants. Region of living was identified as the most important determinant of prescribing a certain category of antidepressant drugs to first users (OR 2.9 [95%CI 2.5‐3.3]). Just a few patient characteristics were associated with antidepressant drug choice. The elderly were more likely to receive a classic antidepressant, as were patients concomitantly using anti‐epileptics (OR 0.4 [95%CI 0.3‐0.6]). Patients concomitantly using cardiac glycosides were more likely to receive a second generation antidepressant (OR 1.8 [95%CI 1.2‐2.1]). With respect to age and the other patient characteristics studied, the same pattern was observed in both regions. Conclusion: Regional differences contributed more to differences in prescribing habits than individual patient characteristics. In order to improve pharmacotherapy with antidepressant drugs relevant patient characteristics should more be taken into account.

Switch patterns before and after patent expiry of omeprazole: a case study in The Netherlands

An increase of therapeutic substitution after patent expiry might have a negative effect on cost‐savings generated with newly introduced generic drugs. To evaluate influences of patent expiry on therapeutic substitution, switch behaviour before and after patent expiry was investigated.

Patient education to users of oral hypoglycemic agents: the perspective of Dutch community pharmacists

The purpose of this study was to indicate which patient education activities directed at users of oral hypoglycemic agents are desirable in Dutch community pharmacies and to explore which preconditions should be considered when implementing the desired activities. A qualitative study was conducted with a panel composed of seven pharmacists and seven technicians with considerable experience in giving advice to people with diabetes mellitus type 2. A consensus method was used, which consisted of a written questionnaire and a feedback discussion, to determine which activities were considered desirable and to identify which other health care providers should be involved. The way these activities should be implemented was explored by a focus-group discussion. The following goals of patient education activities were studied: 1) adherence to the dosage regimen, 2) adherence to lifestyle advices,3) gaining awareness of effects and 4) self-monitoring. According to the members of the panel, patient education activities should be directed primarily at stimulating adherence to the dosage regimen, increasing awareness of side effects and improving the correct technical use of blood glucose meters. Activities directed at lifestyle advice seemed to be less desirable to the pharmacy staff. Preconditions that should be considered when implementing these activities were structural cooperation with GPs and diabetic nurses and specialization of tasks of pharmacy technicians. Our results indicate that deepening of existing tasks, such as stimulating adherence to the dosage regimen is desirable in developing patient education activities at users of oral hypoglycemic agents.

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

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.